Grayson County was named for William Grayson, a delegate to the Continental Congress from 1784 to 1787 and one of the first two United States senators from Virginia. It was formed from Wythe County by a statute adopted on 7 November 1792. The county court first met on 21 May 1793. A portion of Patrick County was added in 1810. The county seat is Independence.

Throughout the Civil War, the principal responsibility for Virginia's indigent soldiers' families lay with the locality. The Virginia State Convention in 1861 gave the responsibility entirely to counties and incorporated towns and authorized whatever actions had already been taken. Acts of Assembly in 1862 and 1863 expanded the localities' powers to provide for their needy, and in 1863 some minimal state assistance was added in. At first relief was provided as money, but as the monetary system collapsed, relief was distributed in kind. Agents of the court maintained lists of eligible families, gathered goods for distribution and paid for them, and impressed supplies if necessary. Virginia was unique amongst the southern states in that it assigned the provisioning of needy families almost solely to the locality.